Molecular Dynamics of Co-signal Molecules in T-Cell Activation

T-cell activation is induced through the TCR microcluster (TCR-MC), which is generated by dynamically recruiting the TCR, kinases, and adaptors to trigger the full activation signal. Co-stimulation receptors also accumulate, mostly at the TCR-MC, and induce signals that positively and negatively modulate the direction and magnitude of T-cell activation. CD28 initially colocalizes with the TCR-MC but then migrates to a distinct region of the cSMAC called the signaling cSMAC, where it recruits and associates with PKCθ, CARMA1, and Rltpr to induce sustained co-stimulation signals leading to NF-kB activation. Although CTLA-4 and PD-1 mediate inhibitory functions in T-cell activation, their molecular dynamics are quite different. Both are expressed only after activation, when they function as feedback inhibition of T-cell activation. Whereas PD-1 initially accumulates in the TCR-MC and then moves to the cSMAC, CTLA-4 directly accumulates at the cSMAC. PD-1 inhibits activation by inducing dephosphorylation of TCR-upstream signaling molecules by transiently recruiting SHP2, whereas CTLA-4 competes with CD28 for CD80/86 binding within the signaling cSMAC. In general, for both positive and negative co-stimulation, these co-stimulation receptors are also clustered in a ligand-dependent fashion, and their colocalization with the TCR-MC is required to mediate co-stimulation signals.